Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA.

Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Research Abstract Details 

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Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Abstract Text:

Yan Zhang,Nilesh W Gaikwad,Kevin Olson,Muhammad Zahid,Ercole L Cavalieri,Eleanor G Rogan,

Accumulating evidence suggests that specific metabolites of estrogens, namely, catechol estrogen quinones, react with DNA to form adducts and generate apurinic sites, which can lead to the mutations that induce breast cancer. Oxidation of estradiol (E(2)) produces 2 catechol estrogens, 4-hydroxyestradiol (4-OHE(2)) and 2-OHE(2) among the major metabolites. These, in turn, are oxidized to the quinones, E(2)-3,4-quinone (E(2)-3,4-Q) and E(2)-2,3-Q, which can react with DNA. Oxidation of E(2) to 2-OHE(2) is mainly catalyzed by cytochrome P450 (CYP) 1A1, and CYP3A4, whereas oxidation of E(2) to 4-OHE(2) in extrahepatic tissues is mainly catalyzed by CYP1B1 as well as some CYP3As. The potential involvement of CYP isoforms in the further oxidation of catechols to semiquinones and quinones has, however, not been investigated in detail. In this project, to identify the potential function of various CYPs in oxidizing catechol estrogens to quinones, we used different recombinant human CYP isoforms, namely, CYP1A1, CYP1B1, and CYP3A4, with the scope of oxidizing the catechol estrogens 2-OHE(2) and 4-OHE(2) to their respective estrogen quinones, which then reacted with DNA. The depurinating adducts 2-OHE(2)-6-N3Ade, 4-OHE(2)-1-N3Ade, and 4-OHE(2)-1-N7Gua were observed in the respective reaction systems by ultraperformance liquid chromatography/tandem mass spectrometry. Furthermore, more than 100-fold higher levels of estrogen-glutathione (GSH) conjugates were detected in the reactions. Glutathione conjugates were observed, in much smaller amounts, when control microsomes were used. Depurinating adducts, as well as GSH conjugates, were obtained when E(2)-3,4-Q was incubated with CYP1B1 or control microsomes in a 30-minute reaction, further demonstrating that GSH is present in these recombinant enzyme preparations. These experiments demonstrated that CYP1A1, CYP1B1, and CYP3A4 are able to oxidize catechol estrogens to their respective quinones, which can further react with GSH, protein, and DNA, the last resulting in depurinating adducts that can lead to mutagenesis.

Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Publishing Authors By Initials

Y Zhang,NW Gaikwad,K Olson,M Zahid,EL Cavalieri,EG Rogan,

For similar organic chemicals: quinones research abstracts see: organic chemicals: quinones research

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Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Metabolism: clinical and experimental

VOLUME: 56

Page Numbers: 887-94

Journal Abbreviation: Metab. Clin. Exp.

ISSN: 0026-0495

DAY: 3

MONTH: Jul

YEAR: 2007

Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Information

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LANGUAGE: eng

NlmUniqueID: 375267

Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Keywords Mesh Terms:

KEYWORDS: Quinones

MESH TERMS: metabolism

Chemical & Substance for Abstract: Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Information

Substance Name: cytochrome P-450 CYP1B1

Registry Number: EC 1.14.14.1

Grant and Affiliation Information for Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA.

AFFILIATION: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.

Country: United States

AGENCY: United States NCI

GRANT: P30 CA36727

ACRONYM: CA

MEDLINETA: Metabolism

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